The long-term goal of these studies is to understand the mechanisms by which viruses evade or suppress the immune response and persist in the host. The mechanism of viral persistence remains a major unresolved problem in virology. While the reported incidence of several acute viral infections has declined in recent years, the incidence of persistent viral infections has been increasing. This is most dramatically illustrated by the acquired immune deficiency syndrome (AIDS). Chronic hepatitis B virus infections have also steadily increased with current estimates of over 200 million virus carriers. In addition, persistent viral infections have been associated with certain neoplasms and immunopathological diseases. Infection of mice with lymphocytic choriomeningitis virus (LCMV) provides an excellent model for studying the interaction between the virus and the immune system of it's natural host, and in defining conditions that lead to viral clearance or persistence. The objectives of the proposed research are two-fold. First, to analyze the genetic differences between wild type LCMV and LCMV variants and to identify the precise location of the mutations that allow these varients to suppress virus specific T cell responses and cause persistent infections in adult mice. Second, to examine the interaction of the variants with T cells and macrophages to elucidate the mechanism of immunosuppression. These studies, combining the disciplines of virology and immunology, should lead to an improved fundamental understanding of the pathogenesis of chronic viral infections